title: Absence of scavenger receptor A promotes dendritic cell-mediated cross-presentation of cell-associated antigen and antitumor immune response.
abstract: Given the primary expression of scavenger receptor A (SRA) or CD204 on antigen-presenting cells, we investigate the immunoregulatory activities of SRA/CD204 in the context of cross-presentation of cell-associated antigen and the immunogenicity of dying tumor cells. Immunization with dying prostate cancer cells results in profoundly increased control of subsequently inoculated tumors in SRA/CD204 knockout mice. Using OVA-expressing RM1 prostate tumor line (RM1-OVA), we show for the first time that SRA absence greatly enhances dendritic cells (DCs)-mediated cross-presentation of OVA antigen derived from dying RM1 cells. While the phagocytic ability of DCs is not significantly impacted by the lack of SRA/CD204, DCs deficient in SRA/CD204 display increased expression of inflammatory cytokines and chemokines, as well as co-stimulatory molecules upon interaction with dying RM1 cells, implicating a suppressive regulation of the functional activation of DCs by SRA/CD204. Further, SRA/CD204-deficient DCs pulsed with dying RM1-OVA cells are more effective than wild-type counterparts in priming antigen-specific T-cell responses, resulting in improved control of RM1 tumor growth in both prophylactic and therapeutic settings. Our findings suggest that the increased immunogenicity of dying tumor cells in SRA/CD204 knockout mice is attributed to the altered functions of DCs in the absence of SRA/CD204, which underscores the important role of SRA/CD204 in host immune homeostasis. Selective downregulation or blockade of this immunoregulatory molecule may lead to enhanced potency of DC-based vaccines capable of breaking immune tolerance against cancer.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.forename: Huanfa
authors.initials: H
authors.lastname: Yi
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yu
authors.forename: Fanlei
authors.initials: F
authors.lastname: Hu
authors.forename: Daming
authors.initials: D
authors.lastname: Zuo
authors.forename: John R
authors.initials: JR
authors.lastname: Subjeck
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive / Q000379:methods; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D051117:Scavenger Receptors, Class A / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology
chemical_list: D000941:Antigens; D016207:Cytokines; D018836:Inflammation Mediators; C495140:Msr1 protein, mouse; D051117:Scavenger Receptors, Class A; D010047:Ovalbumin